End-stage glomerulosclerosis constitutes a major complication of diabetes mellitus. The fact that the glomerular lesions in both IDDM and NIDDM are similar suggests that abnormalities in glucose metabolism may participate in their development. Hyperglycemia leads to the accumulation of advanced glycosylation end-products. These products participate in abnormal, non-metabolizable cross-linking of extra- cellular matrix components. Their accumulation may contribute to the sclerosis observed in diabetics. AGEs trigger a large number of biological reactions which are mediated by surface receptors that have been characterized on macrophages, endothelial cells, and human and rat mesangial cells. Using normal mouse mesangial cells, we showed that cells exposed to AGE had increased levels of the following mRNAs using the RNAse protection assay: collagen type IV, proteoglycan heparan sulfate, and laminin A and B chains. We also found an increased release of collagen type IV into the medium. We explored the effects of injections of AGEs to the intact animal would have similar effects. normal rats receiving long-term injections of AGE-Albumin had albuminuria and developed focal sclerotic glomerular lesions. The coadministration of aminoguanidine which inhibits crosslinking of AGEs prevented the renal lesions. We also found that the glomeruli of normal mice receiving repeated injections of AGEs exhibited an increase in mRNAs coding for alpha-1 type IV collagen and for the B1 chain of laminin establishing that there is a glomerular response to AGEs in vivo. These responses were associated with an increase in TGF-beta-1 but not PDGF message level. These responses did not occur when the mice were cotreated with aminoguanidine.
